Tissue-free liquid biopsies combining genomic and methylation signals for minimal residual disease detection in patients with early colorectal cancer from the UK TRACC Part B study.

PURPOSE: Absence of post-operative circulating tumour DNA (ctDNA) identifies resected colorectal cancer (CRC) patients with low recurrence risk for adjuvant chemotherapy (ACT) de-escalation. We present the largest resected CRC cohort to date with tissue-free minimal residual disease (MRD) detection. DESIGN: TRACC included stage I-III resectable CRC patients. Prospective longitudinal plasma collection for ctDNA occurred pre- and post-surgery, post-ACT, every 3m for year 1 and every 6m in years 2 and 3 with imaging annually. The Guardant Reveal assay evaluated genomic and methylation signals. The primary endpoint was 2yr recurrence free survival (RFS) by post-operative ctDNA detection. (NCT04050345) Results: Between December 2016 and August 2022, 1203 were patients enrolled. Plasma samples (n=997) from 214 patients were analysed. 143 patients were evaluable for the primary endpoint; 92 (64.3%) colon, 51 (35.7%) rectal; 2 (1.4%) stage I, 64 (44.8%) stage II, 77 (53.8%) stage III. Median follow-up was 30.3m (95% CI: 29.5-31.3). 2yr RFS was 91.1% in patients with ctDNA not detected post-operatively and 50.4% in those with ctDNA detected (HR 6.5 [2.96-14.5] p<0.0001). Landmark negative predictive value (NPV) was 91.2% (95% CI 83.9-95.9). Longitudinal sensitivity and specificity were 62.1% (95% CI 42.2-79.3) and 85.9% (95% CI 78.9-91.3) respectively. Median lead-time from ctDNA detection to radiological recurrence was 7.3m (IQR 3.3-12.5; n=9). CONCLUSIONS: Tissue-free MRD detection with longitudinal sampling predicts recurrence in stage I-III CRC without need for tissue sequencing. NPV is high supporting ACT de-escalation in patients with ctDNA not detected post-operatively, now being investigated in the UK TRACC Part C study.

From diagnosis of colorectal cancer to diagnosis of Lynch syndrome: The RM Partners quality improvement project.

AIM: The UK National Institute for Health and Care Excellence guideline DG27 recommends universal testing for Lynch syndrome (LS) in all newly diagnosed colorectal cancer (CRC) patients. However, DG27 guideline implementation varies significantly by geography. This quality improvement project (QIP) was developed to measure variation and deliver an effective diagnostic pathway from diagnosis of CRC to diagnosis of LS within the RM Partners (RMP) West London cancer alliance. METHOD: RM Partners includes a population of 4 million people and incorporates nine CRC multidisciplinary teams (MDTs), overseen by a Pathway Group, and three regional genetic services, managing approximately 1500 new CRC cases annually. A responsible LS champion was nominated within each MDT. A regional project manager and nurse practitioner were appointed to support the LS champions, to develop online training packages and patient consultation workshops. MDTs were supported to develop an 'in-house' mainstreaming service to offer genetic testing in their routine oncology clinics. Baseline data were collected through completion of the LS pathway audit of the testing pathway in 30 consecutive CRC patients from each CRC MDT, with measurement of each step of the testing pathway. Areas for improvement in each MDT were identified, delivered by the local champion and supported by the project team. RESULTS: Overall, QIP measurables improved following the intervention. The Wilcoxon signed rank test revealed significant differences with strong effect sizes on the percentile of CRC cases undergoing mismatch repair (MMR) testing in endoscopic biopsies (p = 0.008), further testing with either methylation or BRAF V600E (p = 0/03) and in effective referral for genetic testing (from 10% to 74%; p = 0.02). During the QIP new mainstreaming services were developed, alongside the implementation of systematic and robust testing pathways. These pathways were tailored to the needs of each CRC team to ensure that patients with a diagnosis of CRC had access to testing for LS. Online training packages were produced which remain freely accessible for CRC teams across the UK. CONCLUSION: The LS project was completed by April 2022. We have implemented a systematic approach with workforce transformation to facilitate identification and 'mainstreamed' genetic diagnosis of LS. This work has contributed to the development of a National LS Transformation Project in England which recommends local leadership within cancer teams to ensure delivery of diagnosis of LS and integration of genomics into clinical practice.

Role of the faecal immunochemical test in patients with risk-stratified suspected colorectal cancer symptoms: A systematic review and meta-analysis to inform the ACPGBI/BSG guidelines.

Background: The UK National Institute for Health and Care Excellence (NICE), recommended in 2017 the use of the faecal immunochemical test (FIT) to guide investigations in patients presenting with NICE-defined low-risk symptoms suspicious for colorectal cancer (CRC). At that time, NICE did not recommend FIT use for high-risk symptoms. This is the first systematic review to evaluate the diagnostic accuracy of FIT in NICE-defined high and low-risk symptoms and was designed to inform the joint ACPGBI/BSG guidelines. Methods: We performed a systematic literature review and meta-analysis. PROSPERO registration number CRD42021224674. Medline and EMBASE databases were searched from inception to 31st March 2022. We included studies recruiting adult patients presenting with suspected CRC symptoms in whom FIT was performed and diagnostic accuracy data for CRC detection could be derived at a limit of detection (LoD) and/or 10 µg haemoglobin/gram faeces threshold in four commonly used analysers. FIT performance was assessed for high-risk, low-risk and individual symptoms where possible. Bivariate meta-analysis was performed where study numbers allowed. Findings: Thirty-one studies (79566 patients) met inclusion criteria. At 10 µg/g, for "all symptoms" (n = 35,945) sensitivity and specificity were 91.0% (95% CI: 88.9, 92.7) and 75.2% (95% CI: 69.6, 80.1); for "high-risk" symptoms (n = 18,264), 88.7% (95% CI: 84.4, 92.0) and 78.5% (95% CI: 73.0, 83.2); and for "low-risk" symptoms (n = 2161), 88.7% (95% CI: 78.1, 95.3) and 88.5% (95% CI: 87.1, 89.9), respectively. At LoD, for "all symptoms" (n = 26,056) sensitivity and specificity were 94.7% (95% CI: 90.5, 97.1) and 66.5% (95% CI: 58.7, 73.6); for "high-risk" symptoms (n = 16,768), 92.8% (95% CI: 86.4, 96.3) and 70.3% (95% CI: 66.5, 73.8); and for "low-risk" symptoms (n = 2082), 94.7% (95% CI: 85.4, 98.9) and 71.9% (95% CI: 69.9, 73.9), respectively. Summary estimates were similar across different analysers. Interpretation: FIT sensitivity for CRC detection is maximised at the LoD; its performance is similar in high and low-risk symptoms, and across different analysers where a common threshold is used. FIT performance for CRC detection is adequate and transferrable to clinical diagnostic pathways. Funding: This review was part-funded by NHS England awarded to RM Partners. RB and RC were funded by research fellowships awarded by Croydon University Hospital.

Introduction of an integrated primary care faecal immunochemical test referral pathway for patients with suspected colorectal cancer symptoms.

AIM: To determine the efficacy of a new 2-week wait pathway that uses the faecal immunochemical test (FIT) in primary care to triage patients with high and low risk symptoms suspicious of colorectal cancer (CRC). This service improvement pilot follows 2017 National Institute for Health and Care Excellence guidance, that recommended using FIT to guide referral of patients with low risk, but not high risk symptoms, which continue to be referrred on the 2-week pathway. METHOD: Patients with high- and low-risk CRC symptoms were tested with FIT and those with faecal haemoglobin (f-Hb) ≥9.5 µg haemoglobin/g faeces (hereafter µg/g) were referred to secondary care. Results were tracked and primary care prompted to refer if timely referral was not made. RESULTS: Between December 2019 and October 2020, 5672 patients presented to primary care with high and/or low risk symptoms warranting investigations. Of these, 622 (11%) patients were referred without a FIT, of whom 36 (5.8%) had CRC. The remaining 5050 patients had a FIT, of which 4187 (83%) were processed to produce a quantitative result. Of these, 1085 patients (25.9%) had an f-Hb ≥9.5 µg/g and of those, 982 patients (90.5%) were referred and 56 (5.7%) had CRC. A total of 3102 patients (74.1%) had an f-Hb <9.5 µg/g, of which 456 (14.7%) were referred and three (0.7%) had CRC. A total of 97 cancers were diagnosed with a cancer prevalence of 1.7%. CONCLUSION: A 2-week wait pathway incorporating FIT as a triage tool can be implemented successfully in primary care to identify symptomatic patients at highest risk of CRC.

Faecal immunochemical testing (FIT) in patients with signs or symptoms of suspected colorectal cancer (CRC): a joint guideline from the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and the British Society of Gastroenterology (BSG).

Faecal immunochemical testing (FIT) has a high sensitivity for the detection of colorectal cancer (CRC). In a symptomatic population FIT may identify those patients who require colorectal investigation with the highest priority. FIT offers considerable advantages over the use of symptoms alone, as an objective measure of risk with a vastly superior positive predictive value for CRC, while conversely identifying a truly low risk cohort of patients. The aim of this guideline was to provide a clear strategy for the use of FIT in the diagnostic pathway of people with signs or symptoms of a suspected diagnosis of CRC. The guideline was jointly developed by the Association of Coloproctology of Great Britain and Ireland/British Society of Gastroenterology, specifically by a 21-member multidisciplinary guideline development group (GDG). A systematic review of 13 535 publications was undertaken to develop 23 evidence and expert opinion-based recommendations for the triage of people with symptoms of a suspected CRC diagnosis in primary care. In order to achieve consensus among a broad group of key stakeholders, we completed an extended Delphi of the GDG, and also 61 other individuals across the UK and Ireland, including by members of the public, charities and primary and secondary care. Seventeen research recommendations were also prioritised to inform clinical management.

A comparison of the faecal haemoglobin concentrations and diagnostic accuracy in patients suspected with colorectal cancer and serious bowel disease as reported on four different faecal immunochemical test systems.

OBJECTIVES: Faecal immunochemical tests for haemoglobin (FIT) are used in colorectal cancer (CRC) screening programmes and to triage patients presenting with symptoms suggestive of CRC for further bowel investigations. There are a number of quantitative FIT analytical systems available. Currently, there is no harmonisation or standardisation of FIT methods. The aim of the study was to assess the comparability of numerical faecal haemoglobin concentrations (f-Hb) obtained with four quantitative FIT systems and the diagnostic accuracy at different f-Hb thresholds. METHODS: A subgroup of the National Institute for Health and Care Excellence (NICE) FIT study, a multicentre, prospective diagnostic accuracy study were sent four FIT specimen collection devices from four different FIT systems or two FIT devices for one FIT system. Faecal samples were examined and analysis of results carried out to assess difference between methods at thresholds of limit of detection (LoD), 10 µg haemoglobin/g faeces (µg/g) and 100 µg/g. RESULTS: 233 patients returned specimen collection devices for examination on four different systems; 189 patients returned two FIT kits for one system. At a threshold of 100 µg/g the sensitivity is the same for all methods. At lower thresholds of LoD and 10 µg/g differences were observed between systems in terms of patients who would be referred and diagnostic accuracies. CONCLUSIONS: The lack of standardisation or harmonisation of FIT means that differences are observed in f-Hb generated on different systems. Further work is required to understand the clinical impact of these differences and to minimise them.

MRI-Diagnosed Tumor Deposits and EMVI Status Have Superior Prognostic Accuracy to Current Clinical TNM Staging in Rectal Cancer.

SUMMARY BACKGROUND DATA: MRI assessment of rectal cancer not only assesses tumor depth and surgical resectability but also extramural disease which affects prognosis. We have observed that nonnodal tumor nodules (tumor deposits; mrTDs) have a distinct MRI appearance compared to lymph node metastases (mrLNMs). OBJECTIVE: We aimed to assess whether mrTDs and mrLNMs have different prognostic implications and compare these to other known prognostic markers. METHODS: This was a retrospective cohort study of 233 patients undergoing resection for rectal cancer from January 2007 to October 2015. Data were obtained from electronic records and MRIs blindly rereported. Survival was determined using Kaplan-Meier method. Prognostic markers were evaluated using Cox regression and competing risks analysis. Inter-observer agreement for mrTD was measured using Cohen Kappa. RESULTS: On multivariable analysis, baseline mrTD/mrEMVI (extramural venous invasion) status was the only significant MRI factor for adverse survival [hazard ratio (HR) 2.36 (1.54-3.61] for overall survival, 2.37 (1.47-3.80) for disease-free survival (both P < 0.001), superseding T and N categories. mrLNMs were associated with good prognosis (HR 0.50 (0.31-0.80) P = 0.004 for overall survival, 0.60 (0.40-0.90) P = 0.014 for disease-free survival). On multivariable analysis, mrTDs/mrEMVI were strongly associated with distant recurrence (HR 6.53 (2.52-16.91) P ≤ 0.001) whereas T and N category were not. In a subgroup analysis of posttreatment MRIs in postchemoradiotherapy patients, mrTD/mrEMVI status was again the only significant prognostic factor; furthermore those who showed a good treatment response had a prognosis similar to patients who were negative at baseline. Inter-observer agreement for detection of mrTDs was k0.77 and k0.83. CONCLUSIONS: Current MRI staging predicting T and N status does not adequately predict prognosis. Positive mrTD/mrEMVI status has greater prognostic accuracy and would be superior in determining treatment and follow-up protocols. Chemoradiotherapy may be a highly effective treatment strategy in mrTD/mrEMVI positive patients.

Faecal immunochemical test for suspected colorectal cancer symptoms: patient survey of usability and acceptability.

BACKGROUND: Recent evidence suggests that the faecal immunochemical test (FIT) can rule out colorectal cancer (CRC) in symptomatic patients. To date, there is no research on usability and perception of FIT for these patients. AIM: To measure variation in attitudes and perception of FIT in patients with suspected CRC symptoms. DESIGN & SETTING: A cross-sectional survey of a subset of participants of the NICE FIT study. METHOD: A questionnaire was co-developed with patients covering four themes on a Likert scale: FIT feasibility, faecal aversion, patient knowledge, and future intentions. Questionnaire and FIT kits were sent to patients with suspected CRC symptoms participating in the NICE FIT study. Logistic regression explored differences in patients' test perception by ethnic group, language, age, location, deprivation, FIT use, and previous experience. RESULTS: A total of 1151 questionnaires were analysed; 90.2% (95% confidence interval [CI] = 88.3% to 91.8%) of patients found faecal collection straightforward, 76.3% (95% CI = 73.7% to 78.6%) disagreed FIT was unhygienic, and 78.1% (95% CI = 75.6% to 80.4%) preferred FIT to colonoscopy. Preference for FIT over colonoscopy was weaker in patients aged 40-64 years than those >65 years (odds ratio [OR] 0.60; 95% CI = 0.43 to 0.84). Intention to use FIT again was stronger in patients who successfully used FIT than those unsuccessful (OR 11.08; 95% CI = 2.74 to 44.75), and white compared with non-white patients assessed (OR 3.20; 95% CI = 1.32 to 7.75). CONCLUSION: While most patients found FIT practical and hygienic, perception differences were found. Strategies to engage patients with more negative FIT perception should underpin symptomatic FIT pathways.

Finding the needle in the haystack: the diagnostic accuracy of the faecal immunochemical test for colorectal cancer in younger symptomatic patients.

AIM: Detection of early onset colorectal cancer is challenging, and remains a rare diagnosis amongst younger people with gastrointestinal symptoms. We investigated whether faecal immunochemical testing (FIT) could identify younger patients at higher risk of colorectal cancer or serious bowel disease including colorectal cancer, inflammatory bowel disease or advanced adenomas. METHODS: A subgroup analysis was performed of symptomatic patients under 50 years of age (<50) from the NICE FIT study, a multicentre, prospective diagnostic accuracy study of FIT conducted between October 2017 and December 2019. The diagnostic accuracy of FIT for colorectal cancer and serious bowel disease was investigated in younger patients at different faecal haemoglobin (f-Hb) cut-offs of 2, 10 and 150 µg blood/g faeces (µg/g). RESULTS: Early onset colorectal cancer was diagnosed in 1.5% (16/1103) of younger symptomatic patients. The sensitivity of FIT for younger patients aged <50 was 87.5% (95% CI 61.7%-98.4%), 81.3% (54.4%-96.0%) and 68.8% (41.3%-89.0%) at f-Hb cut-offs of 2, 10 and 150 µg/g, respectively. The positive predictive value for colorectal cancer increased from 4.2% (2.3%-6.9%) to 11.5% (5.9%-19.6%) at cut-offs of 2 and 150 µg/g, while the positive predictive value for serious bowel disease increased from 31.3% (26.3%-36.5%) to 65.6% (55.2%-75.0%) at the same cut-offs. The negative predictive value of FIT for colorectal cancer remained above 99.5% at all cut-offs. CONCLUSION: Detectable f-Hb on FIT in symptomatic younger patients may indicate referral for investigation of colorectal cancer and serious bowel disease.

Prognostic Importance of MRI-Detected Extramural Venous Invasion in Rectal Cancer: A Literature Review and Systematic Meta-Analysis.

PURPOSE: Extramural venous invasion (EMVI) is recognized as a poor prognostic factor in rectal cancer. There are well-documented limitations associated with pathology detection of EMVI, including variable reporting and the inability to use it preoperatively to guide neoadjuvant treatment. Magnetic resonance imaging (MRI)-detected EMVI (mrEMVI) has been proposed as an imaging biomarker. This review assesses the prognostic significance of mrEMVI on survival outcomes and whether regression of mrEMVI after neoadjuvant therapy is associated with improvements in survival. METHODS AND MATERIALS: An electronic search was carried out using MEDLINE and EMBASE databases using the search terms "rectum," "cancer,", "MRI," and "outcomes." A systematic review and meta-analysis were carried out in accordance with Preferred Reporting for Systematic Reviews and Meta-Analyses guidelines using Review Manager software. A qualitative review was performed. RESULTS: A total of 7399 articles were identified, of which 33 were relevant to the review question. After a qualitative assessment, 20 articles were included in the meta-analysis. Baseline mrEMVI positivity is associated with significantly worsened overall survival (hazard ratio [HR] 1.84; 95% confidence interval [CI], 1.33-2.54; P = .0001) and significantly worsened disease-free survival (HR 2.41; 95% CI, 2.02-2.89; P < .00001). After neoadjuvant treatment, a positive mrEMVI status is associated with a significantly worsened overall and disease-free survival. Only 3 papers specifically looked at mrEMVI regression, but the results show that persistent mrEMVI-positive status after treatment is associated with significantly worsened disease-free survival compared with a change in mrEMVI from positive to negative (HR 1.93; 95% CI, 1.39-2.68; P < .0001). A subgroup analysis of MRI-detected lymph node metastases showed no significant association with survival, with a hazard ratio of 1.33 (95% CI, 0.98-1.80; P = .06). CONCLUSION: mrEMVI is significantly associated with worsened survival outcomes, both at baseline and after neoadjuvant treatment. Additionally, there is evidence that regression of mrEMVI after neoadjuvant treatment is associated with improved survival compared with mrEMVI persistence. The findings of this review emphasize the need for accurate and consistent reporting of mrEMVI status before and after neoadjuvant treatment and support the inclusion of mrEMVI into staging systems preferentially over lymph node metastases.

Local recurrence in sigmoid cancer is a hidden problem, could CT prognostic factors be of value in their prevention? A multi-centre study of 414 patients.

INTRODUCTION: The incidence and patterns of local recurrence of colon cancer are not well reported. The aim of this study was to investigate the contemporary rates and patterns of local recurrence after sigmoid cancer resection, comparing pre and post-operative biomarkers in predicting local disease recurrence. MATERIALS AND METHODS: A multi-centre, retrospective analysis of 414 patients undergoing resectional surgery for sigmoid colon cancer was conducted. Multivariable Cox Proportional Hazard models were created to identify variables associated with local disease recurrence. Patterns of recurrence and prognostic significance of pre and post-operative variables were identified. RESULTS: In 414 patients, the local recurrence rate was 12.6%. The R1/R2 rate was 2.4%. Local recurrence occurred most commonly within the peri-anastomotic region (50%), followed by the peritoneum (33%). On multivariate analysis, local recurrence was predicted by pathological T stage (HR 1.15) and R1 resection (HR 2.95), but also computerised tomography (CT) identified tumour deposits (HR 2.40) and local peritoneal infiltration (2.70). CONCLUSIONS: Contemporary local recurrence rates for sigmoid cancer are high at 12.6%. Outcomes may be improved if local recurrence is reduced at the most common sites such as the peri-anastomotic area or peritoneum. Extra-nodal CT-imaging biomarkers of local peritoneal infiltration and tumour deposits were prognostically significant on multivariate analysis in addition to pathology staging variables.

Using the faecal immunochemical test in patients with rectal bleeding: evidence from the NICE FIT study.

AIM: The aim of this work was to investigate whether the faecal immunochemical test (FIT) could safely rule out colorectal cancer (CRC) in patients with rectal bleeding (RB). METHOD: This was a multicentre, double-blinded diagnostic accuracy study in 50 National Health Service hospitals. Patients referred from primary care with suspected CRC on an urgent 2-week-wait pathway were asked to perform a FIT prior to colonoscopy. The primary outcome measure was the sensitivity of the FIT for CRC in patients with RB versus nonrectal bleeding symptoms (NRB). The secondary outcome measures included the diagnostic accuracy of the FIT for CRC and other serious bowel disease. RESULTS: Of 9822 patients included in the study, 3143 (32.0%) were referred with RB. CRC was present in 4.7% of patients with RB versus 2.7% of patients with NRB (p < 0.05). Faecal haemoglobin (f-Hb) was detectable (>2 µg/g) in 44.1% of patients with RB and 33.9% with NRB (p < 0.05). In RB patients, CRC was present in 10.4% when f-Hb was >2 µg/g compared with 0.1% when f-Hb was not detected. Flexible sigmoidoscopy in this group would further reduce the risk of CRC to 0.03%. The sensitivity of the FIT for CRC in RB versus NRB groups was 98.6% (95% CI 95.2%-99.8%) vs 95.6% (91.5%-98.1%) for f-Hb >2 µg/g and 96.6% (92.2%-98.9%) vs 86.3 (80.4%-90.9%) for f-Hb >10 µg/g. CONCLUSION: Faecal haemoglobin is not always detectable in patients with RB; 56% of patients had undetectable f-Hb (<2 µg/g) and CRC was present in 0.1%. The high sensitivity of the FIT can be used to rule out CRC in patients with RB and triage them more appropriately for investigation.

Histopathological diagnosis of tumour deposits in colorectal cancer: a Delphi consensus study.

AIMS: Tumour deposits (TDs) are an important prognostic marker in colorectal cancer. However, the classification, and inclusion in staging, of TDs has changed significantly in each tumour-node-metastasis (TNM) edition since their initial description in TNM-5, and terminology remains controversial. Expert consensus is needed to guide the future direction of precision staging. METHODS AND RESULTS: A modified Delphi consensus process was used. Statements were formulated and sent to participants as an online survey. Participants were asked to rate their agreement with each statement on a five-point Likert scale and also to suggest additional statements for discussion. These responses were circulated together with anonymised comments, and statements were modified prior to carrying out a second online round. Consensus was set at 70%. Overall, 32 statements reached consensus. There were concerns that TDs were currently incorrectly placed in the TNM system and that their prognostic importance was being underestimated. There were concerns regarding interobserver variation and it was felt that a clearer, more reproducible definition of TDs was needed. CONCLUSIONS: Our main recommendations are that the number of TDs should be recorded even if lymph node metastases (LNMs) are also present and that nodules with evidence of origin [extramural venous invasion (EMVI), perineural invasion (PNI), lymphatic invasion (LI)] should still be categorised as TDs and not excluded, as TNM-8 specifies. Whether TDs should continue to be included in the N category at all is controversial, and did not achieve consensus; however, participants agreed that TDs are prognostically worse than LNMs and the N1c category is suboptimal, as it does not reflect this.

Faecal immunochemical test is superior to symptoms in predicting pathology in patients with suspected colorectal cancer symptoms referred on a 2WW pathway: a diagnostic accuracy study.

OBJECTIVE: To assess whether a faecal immunochemical test (FIT) could be used to select patients with suspected colorectal cancer (CRC) symptoms for urgent investigation. DESIGN: Multicentre, double-blinded diagnostic accuracy study in 50 National Health Service (NHS) hospitals across England between October 2017 and December 2019. Patients referred to secondary care with suspected CRC symptoms meeting NHS England criteria for urgent 2 weeks wait referral and triaged to investigation with colonoscopy were invited to perform a quantitative FIT. The sensitivity of FIT for CRC, and effect of relevant variables on its diagnostic accuracy was assessed. RESULTS: 9822 patients were included in the final analysis. The prevalence of CRC at colonoscopy was 3.3%. The FIT positivity decreased from 37.2% to 19.0% and 7.6%, respectively, at cut-offs of 2, 10 and 150 µg haemoglobin/g faeces (µg/g). The positive predictive values of FIT for CRC at these cut-offs were 8.7% (95% CI, 7.8% to 9.7%), 16.1% (95% CI 14.4% to 17.8%) and 31.1% (95% CI 27.8% to 34.6%), respectively, and the negative predictive values were 99.8% (95% CI 99.7% to 99.9%), 99.6% (95% CI 99.5% to 99.7%) and 98.9% (95% CI 98.7% to 99.1%), respectively. The sensitivity of FIT for CRC decreased at the same cut-offs from 97.0% (95% CI 94.5% to 98.5%) to 90.9% (95% CI 87.2% to 93.8%) and 70.8% (95% CI 65.6% to 75.7%), respectively, while the specificity increased from 64.9% (95% CI 63.9% to 65.8%) to 83.5% (95% CI 82.8% to 84.3%) and 94.6% (95% CI 94.1% to 95.0%), respectively. The area under the receiver operating characteristic curve was 0.93 (95% CI 0.92 to 0.95). CONCLUSION: FIT sensitivity is maximised to 97.0% at the lowest cut-off (2 µg/g); a negative FIT result at this cut-off can effectively rule out CRC and a positive FIT result is better than symptoms to select patients for urgent investigations. TRIAL REGISTRATION NUMBER: ISRCTN49676259.

Prioritisation by FIT to mitigate the impact of delays in the 2-week wait colorectal cancer referral pathway during the COVID-19 pandemic: a UK modelling study.

OBJECTIVE: To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic. DESIGN: We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval. RESULTS: Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%. CONCLUSIONS: Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the appreciable false-negative rate of FIT in symptomatic patients means most colonoscopies will still be required.

Can extranodal tumour deposits be diagnosed on MRI? Protocol for a multicentre clinical trial (the COMET trial).

INTRODUCTION: Tumour deposits (TDs) are a poor prognostic marker when seen on pathology, and are worse than lymph node metastases (LNMs). They are now being reported on MRI as discontinuous nodules of extramural venous invasion but this diagnosis has not been validated and it is unclear how it correlates with the diagnosis of TDs on pathology. METHODS AND ANALYSIS: This is a prospective interventional clinical trial which aims to directly map the location of TDs on MRI and correlate what is seen on MRI with the pathology findings at each location. All patients with rectal cancer undergoing resectional surgery are eligible (including those undergoing preoperative therapy). The primary outcome is the prevalence of TDs seen on pathology. Secondary outcomes are to assess radiological and pathological interobserver agreement, assess the effect of TDs on prognosis and carry out exploratory work looking at differences between TDs and LNMs. The estimated sample size is 100 to detect a twofold increase in the pathological diagnosis of TD when MRI mapping is used. ETHICS AND DISSEMINATION: Ethical approval has been granted from the South Central-Hampshire B Research and Ethics Committee (IRAS 217627). The study will be carried out under standard operative procedures within the Royal Marsden Hospital. TRIAL REGISTRATION NUMBER: NCT03303547.

The sigmoid take-off: An anatomical imaging definition of the rectum validated on specimen analysis.

BACKGROUND: A pre-operative imaging landmark to define the rectum would optimise clinical care of rectal cancer patients and research efforts to improve outcomes. The sigmoid take-off has been suggested as an imaging landmark for the rectosigmoid junction (RSJ). This study aimed to investigate whether this imaging definition of the rectum was validated by surgical specimen analysis. METHODS: This prospective study recruited 20 patients undergoing surgery and undertook radiological and pathological analysis of their rectal specimens. The radiological landmark of the sigmoid take-off was identified on pre-operative magnetic resonance imaging (MRI), and the distance to the anterior peritoneal reflection was measured by two readers. After surgery, the distance from the beginning of the sigmoid mesocolon to the anterior peritoneal reflection to the beginning of the sigmoid mesocolon on the specimen was measured, and compared to the distance on MRI using Pearson's Correlation Coefficient and Bland-Altman plots. RESULTS: In 17 patients, the mean distance from the anterior peritoneal reflection to the RSJ on MRI was 20.3 mm and 23.1 mm for two readers, and on pathology was 20.6 mm. The mean differences between MRI and specimen measurements were -0.31 mm (-2.83 to 2.20 mm), and 2.51 mm (95% confidence interval -0.31 to 5.33 mm) for each reader, with correlation coefficients of 0.77 and 0.81. CONCLUSION: The sigmoid take-off has been validated on specimen analysis to be an imaging landmark that defines the termination of the rectum. This anatomical landmark can be used to classify tumours and guide treatment and research of sigmoid colon and rectal cancer.

Assessment of a Staging System for Sigmoid Colon Cancer Based on Tumor Deposits and Extramural Venous Invasion on Computed Tomography.

Importance: Preoperative TNM stratification of colon cancer on computed tomography (CT) does not identify patients who are at high risk of recurrence that could be selected for preoperative treatment. Objective: To evaluate the utility of CT findings for prognosis of sigmoid colon cancer. Design, Setting, and Participants: This prognostic study used retrospective data from patients who underwent bowel resection for sigmoid colon cancer between January 1, 2006, and January 1, 2015, at a tertiary care center receiving international and national referrals for colorectal cancer. Statistical analysis was performed in April 2019. Main Outcomes and Measures: Cox proportional hazards regression analysis was performed to investigate CT findings associated with disease recurrence. Kaplan-Meier survival plots were calculated for disease-free survival using CT staging systems. Results: Of the 414 patients who had sigmoid colon cancer (248 [60.0%] men; mean [SD] age, 66.1 [12.7] years), with median follow-up of 61 months (interquartile range, 40-87 months), 122 patients (29.5%) developed disease recurrence. On multivariate analysis, nodal disease was not associated with disease recurrence; only tumor deposits (hazard ratio [HR], 1.90; 95% CI, 1.21-2.98; P = .006) and extramural venous invasion (HR, 1.97; 95% CI, 1.26-3.06; P = .003) on CT were associated with disease recurrence. Significant differences in disease-free survival were found using CT-T3 substage classification (HR, 1.88; 95% CI, 1.32-2.68) but not CT-TNM (HR, 1.55; 95% CI, 0.94-2.55). The presence of tumor deposits or extramural venous invasion on CT (HR, 2.45; 95% CI, 1.68-3.56) had the strongest association with poor outcome. Conclusions and Relevance: In this study, T3 substaging and detection of tumor deposits or extramural venous invasion on preoperative CT scans of sigmoid colon cancer were prognostic factors for disease-free survival, whereas TNM and nodal staging on CT had no prognostic value. T3 substaging and detection of tumor deposits or extramural venous invasion of sigmoid colon cancer was superior to TNM on CT and could be used to preoperatively identify patients at high risk of recurrence.